This application is to design and synthesize novel phenylaminotetralin (PAT) compounds as biochemical probes and drugs that target histamine H1-type G protein-coupled receptors (GPCRs) to modulate brain catecholamine neurotransmitter synthesis in neuropsychiatric disorders. Preliminary results suggest PATs are functionally selective ligands that can distinguish and selectively activate brain H1 receptors that couple to the inositol phosphates (IP) vs. cAMP intracellular signaling pathways to modulate tyrosine hydroxylase (TH) activity and catecholamine synthesis. Such ligand-directed functional heterogeneity is proposed for other GPCRs, however, there is a paucity of selective medicinal chemical probes to map the molecular determinants of ligand-receptor interactions that form the molecular basis of differential signaling. Likewise, brain H1 receptors are unexploited as psycho- and neuro-therapeutic targets due to lack of potent, functionally selective agonist ligands that can enter into brain. We developed the stereoselective H1 probe, [3H]-(-)-trans-PAT, that putatively distinguishes the subset of H1 receptors that activate cAMP signaling. Syntheses of 34 PATs is proposed to delineate the PAT-H1 pharmacophore - the specific PAT steric, lipophilic, and electronic chemical determinants for H1 receptor differential binding and signaling. Molecular interaction of PATs with the H1 active site is examined in radioreceptor studies using recombinant human H1 receptors with point mutatations of 13 amino acids hypothesized to be molecular determinants for PAT-H1 binding. We test a hypothesis of ligand-directed functional heterogeneity, i.e., stereochemical and other structural parameters of PATs determines H1 functionally selective binding and activation of IP vs. cAMP signaling to stimulate TH and catecholamine synthesis in mammalian brain. Structure-activity data is correlated using CoMFA 3DQSAR and pharmacophore mapping to develop an H1 receptor model for PAT ligand docking studies. Results will indicate amino acids involved in PAT binding and inferences of H1 receptor 3D structure. QSAR models are iteratively refined to predict PAT chemistry for H1 functionally selective binding and signaling. As most untoward H1-mediated effects proceed via IP signaling, PATs that selectively enhance H1 cAMP signaling will provide a mechanistic basis for exploiting brain H1 receptors as drug targets in neuropsychiatric diseases.